Protease-activated-receptor 1 polymorphisms correlate with risk for unexplained recurrent pregnancy loss: a pilot study querying an association beyond coagulation

Background: Recurrent pregnancy loss (RPL) has been associated with impaired maternal-fetal communication. Protease-activated-receptor 1 (PAR1) is critical for trophoblast invasion and establishment unrelated to its role in vascular biology.

Objectives: To analyze whether polymorphisms of PAR1 [-1426C/T], [-506I/D], and/or IVS[-14A/T] are associated with unexplained RPL.

Patients/methods: A case-control pilot study conducted in 39 healthy women with history of unexplained RPL and 98 women with a full-term, uncomplicated deliveries and no history of RPL.

Results: Women with RPL were significantly more likely to be heterozygous for [-1426C/T] (12.8% versus 3.2%; p=0.049); the heterozygous state for IVS[-14A/T] was also more common (15.4% versus 4.4%; p=0.064). There was no difference between groups for [-506I/D] genotypes. The functional consequence for [-1426C/T] and IVS[-14A/T] polymorphisms is underscored by the markedly low PAR1 mRNA levels in those women. Bioinformatics indicate generation of a new consensus motif for repressor Kruppel-like factor 3 (KLF3) in [-1426T]. Moreover, chromatin immunoprecipitation (ChIP) analysis confirmed a physical association between KLF3 protein and the hPar1 DNA obtained from women with the [-1426C/T] polymorphism.

Conclusions: We hypothesize that the significantly low PAR1 levels impact placenta establishment and consequently pregnancy outcome, thereby profiling a novel risk factor for unexplained RPL.